A subject-matter of the present invention is a process for the preparation of 5-(1-methylethyl)-6-(phenylmethyl)pyrimidine-2,4(1H,3H)-dione of formula (I): 
The compound of formula (I) is known in itself. It can, in particular, be used as intermediate in the synthesis of active compounds which are inhibitors of HIV (Human Immunodeficiency Virus) reverse transcriptase of general formula: 
in which
A represents an RaOCH(Rb)xe2x80x94 group, where Ra is a (C1-6)alkyl group and Rb is a (C1-4)alkyl group or a hydrogen atom.
Various processes for the synthesis of the compounds of formula (II) are disclosed in Patents EP 631 783 and JP 080003143 or in Tanaka H. et al., J. Med. Chem. (1995), 38(15), 2860-2865. The starting material used is 5-(1-methylethyl)pyrimidine-2,4(1H, 3H)-dione, an expensive product which has to be prepared in several stages, including a stage of hydrogenation in a highly dilute acidic medium. 5-(1-Methylethyl)pyrimidine-2,4(1H,3H)-dione then leads to the compound of formula (II) in four synthetic stages: alkylation with chloromethyl ethyl ether, condensation of the lithium salt of the first stage with benzaldehyde at a very low temperature and reduction by hydrogenolysis of the benzyl alcohol derivative thus obtained after acetylation of the alcohol functional group by the action of acetic anhydride. The yields are greater than 70-80%, except during the lithiation stage, which involves operating in a dilute medium, at low temperature, using organometallic reagents, such as butyllithium or hexyllithium.
In Danel K. et al., J. Med. Chem. (1996), 39(12), 2427-2431, another way of carrying out the preparation is described which circumvents the obstacle of the lithiation and uses readily accessible starting materials, such as phenylacetonitrile, to which is added ethyl 2-bromo-2-isopropylacetate via a Reformatsky reaction. The intermediate ethyl 2-isopropyl-4-phenylacetoacetate thus prepared is cyclized to 5-(1-methylethyl)-6-(phenylmethyl)-2-thioxo-2,3-dihydropyrimidine-4(1H)-one by the action of thiourea and then, finally, the compound of formula (I) is obtained by the action of chloroacetic acid. This synthesis is ponderous and involves carrying out a Reformatsky reaction on an industrial scale and thus the use of very large amounts of zinc, which is difficult to employ. Furthermore, the desulphurization of 5-(1-methylethyl)-6-(phenylmethyl)-2-thioxo-2,3-dihydropyrimidine-4(1H)-one with chloroacetic acid is accompanied by the formation of chlorothioacetic acid, a product with a nauseating smell. These processes thus comprise numerous stages and use either expensive starting materials or difficult reaction conditions which involve specific safety conditions.
The Applicant Company has consequently looked for a novel process which obviates the abovementioned disadvantages, making possible simpler, more economical and safer processing.
A first subject-matter of the present invention is consequently a novel process for the preparation of the compounds of formula (I) as defined above and all the alternative forms thereof. Another subject-matter of the invention is novel compounds of use in particular as synthetic intermediates.
The process according to the invention is illustrated by the following scheme: 
In the context of the present application,
M represents an alkali metal or any other metal of Class II and III of the Periodic Classification of the Elements. More particularly, M represents a manganese, tin, zinc, iron, magnesium or copper atom. X represents a halogen atom, such as chlorine, bromine or iodine,
R1 represents a halogen atom or an xe2x80x94OR2 group, where R2 represents a (C1-4)alkyl group,
R3 represents a (C1-4)alkyl group.
The process according to the invention consists in reacting a compound of formula (VI), in which R1 is as defined above, by coupling with an organometallic compound of formula (V), in which M and X are as defined above, in the presence of a homogeneous metal catalyst, in order to obtain the compound of formula (IV) in which R1 is as defined above. This coupling process and all the alternative forms thereof come within the scope of the present invention.
At this point, this compound of formula (IV) can either be directly hydrolysed with a strong acid, in an aqueous medium, in an alcoholic solvent such as ethanol or isopropanol, or, when R1 represents a halogen atom, a dialkoxylation can be carried out by conventional methods known to a person skilled in the art, before carrying out the hydrolysis of this compound obtained of formula (III) under the same hydrolysis conditions as above. This dialkoxylation can be carried out, for example, by the action of alkoxides of formula R3ONa according to methods known to a person skilled in the art or by the action of alcohols of formula R3OH in the presence of a strong base in aqueous solution, such as dilute sodium hydroxide.
The organometallic compound of formula (V) can be chosen, for example, from: a benzylmagnesium halide or a benzylzinc halide. The benzylmagnesium halide is preferred and more particularly benzylmagnesium chloride is preferred.
According to another specific embodiment of the coupling of the compound of formula (VI) with a compound of formula (V), this coupling can be carried out under the conditions of the Barbier reaction (Barbier P., CR, 1899, 128-110), that is to say the addition of a benzyl halide to the compound of formula (VI) in the presence of magnesium turnings, in an appropriate solvent. In the context of the present invention, benzyl chloride is preferred as benzyl halide. This appropriate solvent can be an ether, such as ethyl ether or tetrahydrofuran, or an acetal, such as methylal or ethylal.
According to an advantageous process of the invention, the catalyst is a derivative either of nickel or of palladium. It can be chosen from homogeneous metal catalysts derived either from nickel or from palladium which are complexed with ligands, such as acetylacetone, triarylphosphines or 1,n-bis(diarylphosphino)alkanes, of expanded formula Ni(Acac)2, NiCl2[PR3]2, NiBr2[PR3]2, NiCl2[R2P(CH2)nPR2], Pd[P(R)3]4, PdCl2[PR3]2, and the like, where Acac is the acetylacetonate group and R is a (C1-6)alkyl, aryl or heteroaryl group. The term xe2x80x9caryl groupxe2x80x9d is understood to mean a carbonaceous aromatic nucleus, for example phenyl, naphthyl or anthracenyl, and the term xe2x80x9cheteroaryl groupxe2x80x9d is understood to mean an aromatic heterocycle, such as, for example, pyridine or thiophene. The preferred catalysts have the following expanded formulae: [CH3COCHxe2x95x90C(Oxe2x80x94)CH3]2Ni, NiCl2[(C6H5)2PCH2xe2x80x94CH2P(C6H5)2] or NiCl2[(C6H5)3P]2.
The reaction according to the invention can be carried out in a polar aprotic solvent (such as tetrahydrofuran, isopropyl ether or diethoxymethane) or in a mixture of polar solvents as defined above and nonpolar solvents, such as aromatic hydrocarbons (toluene, heptane, and the like).
The coupling stage, according to either one of the two alternative forms described above, can be carried out at a temperature of between xe2x88x9280 and +110xc2x0 C. Generally, the molar ratio of the compound of formula (VI) to the organometallic compound of formula (V) is between 0.5 and 1.5, preferably between 0.9 and 1.2. When the coupling is carried out under the Barbier conditions as described above, the molar ratio of the compound of formula (VI) to the benzyl halide is between 1 and 3, preferably between 1.1 and 1.5, and he molar ratio of the magnesium to the benzyl halide is between 1 and 5, preferably between 1 and 2. The molar ratio of the compound of formula (VI) to the catalyst can be between lo and 30% by weight with respect to the compound of formula (VI). The strong acid used during the hydrolysis can be chosen from hydrochloric acid, hydrobromic acid, sulphuric acid or alkanesulphonic acid, such as methanesulphonic acid. To a lesser extent, acetic acid can also be used.
The compounds of formula (IV) and (III) are novel and come within the scope of the invention.
The compounds of the invention of formula (VI) where R1 is a chlorine atom, which will be named compounds of formula (VIa), can be prepared according to the following Scheme 2, which uses a procedure known in the literature. 
According to Scheme 2, urea is reacted with diethyl isopropylmalonate (which can be prepared according to conventional methods known to a person skilled in the art or which is alternatively commercially available), in a solvent of alcohol type, at a temperature which can be between 20xc2x0 C. and the reflux temperature of the solvent, in order to obtain 5-(1-methylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione of formula (VII). This compound of formula (VII) is subsequently reacted with phosphorus oxychloride under the conditions described in J. Baddiley et al., J. Chem. Soc., 678(1944), I. Wempen et al., J. Med. Chem., 6(1963), 688-693 or Gershon et al., J. Med. Chem., 7(1964), 808-809, at a temperature of 20 to 160xc2x0 C., in order to obtain 2,4,6-trichloro-5-(1-methylethyl)-pyrimidine of formula (VIa). Following the reaction of the compound (VII) with phosphorus oxychloride, use may particularly be made either of an agent for trapping the acidity, such as a dialkylaniline, or of an amine hydrochloride.
Other procedures known in the literature, for example in H. Koroniak et al., Org. Prep. Proced. Int., 25 (1993), 5 563-568, can also be used in order to obtain 5-(1-methylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione of formula (VII). It is also commercially available.
According to the process of the present invention, the crude products can be used in the successive synthetic stages from the stage involving the compound of formula (VII) to the production of the compound of formula (I).
The compounds of formula (VI), in which R1 is an xe2x80x94OR2 group where R2 represents a (C1-4)alkyl group, can be obtained from 2,4,6-trichloro-5-(1-methylethyl)-pyrimidine of formula (VIa) by dialkoxylation of 2,4,6-trichloro-5-(1-methylethyl)pyrimidine, which can be carried out under the conditions of the dialkoxylation described above.
In order to obtain the compounds of formula (II) in which A represents an RaOCH(Rb)xe2x80x94 group, where Ra is a (C1-6)alkyl group and Rb is a (C1-4)alkyl group or a hydrogen atom, use is made of the method disclosed in Danel K. et al., J. Med. Chem. (1996), 39(12), 2427-2431. This alkylation can also be carried out starting from a compound of formula (I) which is silylated by addition of trimethylsilyl chloride and which is then reacted with an alkoxyalkyl halide. The latter alkylation reaction can be carried out in an aprotic solvent, that is to say either in a halogenated solvent, such as dichloromethane, chloroform or chlorobutane, or in a polar solvent, such as tetrahydrofuran, diethoxymethane, dioxane, and the like. This reaction of alkylation by an alkoxyalkyl halide can also be carried out according to the procedure disclosed in Patent Application Wo 95/18109, whereas, in this patent application, R is an allyl and propargyl group. This reaction is carried out in polar solvents, such as dimethylformamide or dimethyl sulphoxide, in the presence of a base, such as potassium carbonate.
A third subject-matter of the invention is thus a process for the preparation of the compounds of formula (II) from the compound of formula (I) prepared according to the novel process described above.